Background: Pancreatic cancer (PDAC) is an aggressive, deadly disease. Chemotherapy (CT) can improve survival by months, but symptom burden is heavy and quality of life (QOL) is poor. Early palliative care (EPC) alongside standard oncologic care improves QOL and survival in other types of cancer; however, the impact on QOL and symptom burden in advanced PDAC is not known. The primary objective of this study was to test for improvement in QOL between baseline (BL) and 16 weeks (wks) among patients receiving EPC. A secondary objective was to test for decreased symptom burden between BL and 16 wk. Methods: In this prospective case-crossover study, patients >18 years with advanced PDAC received EPC provided by a subspecialist palliative care physician and advanced practice nurse plus standard oncologic care. Ambulatory EPC visits occurred every 2 wks for the first month, then every 4 wks until wk 16, and then as needed. The Functional Assessment of Cancer Therapy – hepatobiliary (FACT-hep) and Edmonton Symptom Assessment System (ESAS) questionnaires were completed at enrollment and every 4 wks until wk 16. Least square means and 95% confidence intervals were computed. A generalized linear mixed model was used to test for statistically significant change in scores between BL and wk 16. A sample size of 20 patients provides 80% power after controlling for covariates; 40 patients were enrolled to account for anticipated attrition and missing data. Results: Of 40 patients, 25 (62.5%) were male, 28 (70%) had metastatic disease, 31 (77.5%) had an ECOG performance status of 0-1, 17 (42.5%) had a body mass index (BMI) >25, 35 (89.7%) had an elevated CA19-9 and 31 (77.5%) received CT. Median age was 70.2 (range 63.0-77.5). BL and wk 16 questionnaires were completed by 100% and 70% of patients, respectively. The mean FACT-hep score at BL was 118.8, compared to 125.7 at wk 16, for a mean change of 6.89, [95%CI (-1.69-15.6); p = 0.11]. The mean change from BL to wk 16 for FACT-hep was statistically significant in patients receiving CT, 10.1 [95%CI (0.32-19.8); p = 0.04], patients with metastatic disease, 14.7 [95%CI (5.30-24.1); p = 0.0030] and patients with a BMI >25, 12.5 [95%CI (1.29-23.7); p = 0.03]. The mean ESAS total symptom score at BL was 25.3, compared to 22.7 at wk 16 (p = 0.28). In those with metastatic disease the mean change was statistically significant, -5.73 [95%CI (-11.21 to -0.24); p = 0.04]. Conclusions: EPC resulted in improved QOL in pts with PDAC receiving CT and those with a BMI >25, and improved QOL and symptom burden in patients with metastatic disease. Given minimal attrition and high rates of questionnaire completion, our sample size was robust, resulting in strong power. Providing palliative care alongside standard oncologic care results in clinically meaningful improvements. Access to palliative care, shortly after diagnosis, should be available for patients with advanced PDAC. Clinical trial information: NCT03837132